Biomedical subjects
Publications and source records attributed to T V Persaud.
We describe a child who was born with marked digital hypoplasia of his right hand. Although the mother was not an epileptic, the child was exposed in utero to diphenylhydantoin.
Mercury is a major environmental pollutant and a proven teratogen in man and animals. Its teratogenicity and effects on fetal chromosomes were investigated in mice. Various dose levels of methylmercuric chloride (MMC) were administered via an intragastric tube to pregnant ICR Swiss/Webster mice on day 9 of gestation. On day 18 of gestation the animals were killed and the fetuses were removed. Fetal lung and liver tissues were processed for cytogenetic studies. Fetuses were also fixed in Bouin's solution for subsequent teratological examination by using Wilson's technique. Mercury levels were determined in maternal blood and randomly selected fetuses. One fetus from each litter was processed for skeletal staining with Alizarin Red S. A significant increase in embryonic deaths and resorptions was observed at all dose levels. The incidence of fetal anomalies was significantly increased following maternal treatment with 10, 15, or 20 mg/kg of MMC. Maternal weight between day 9 and day 18 of gestation decreased significantly. The LD50 of MMC in pregnant mice was determined to be 20 mg/kg of body weight; the LD100 was 30 mg/kg. A significant difference was observed between the mean fetal weights at the various dose levels. Levels of mercury were found to be significantly higher in treated animals and fetuses, and increased in a dose-related manner. The levels of mercury were significantly higher in the fetuses than in the mothers at the same dosage, indicating a correlation between the levels of mercury in maternal mice and corresponding higher levels in their fetuses. Cytogenetic studies revealed significant clumping of chromosomes in metaphase at all dose levels and the frequency of clumping increased as dosage increased. The euploidy number (2n = 40) of chromosomes per cell did not vary between the treatment groups and control groups. The frequency of nucleolus-organizing regions per cell did not change significantly between the treatment groups and the control. The frequency of sister chromatid exchanges increased significantly as the dosage increased.
Varying dose levels of methylmercuric chloride (MMC), 1000 ppm (5 mg through 15 mg/kg of body weight), were administered via an intragastric tube to pregnant ICR Swiss/Webster mice on day 9 of gestation. The animals were killed on gestational day 18 and the fetuses removed. Fetal lung sections were processed for light and electron microscopy. A group of animals treated with physiological saline in a similar manner served as the controls. The fetal lungs from treated animals were hypoplastic and retarded in development. The severity of pulmonary changes increased with the dose-levels of MMC. Vacuolation and lysis of mitochondria were seen in fetal lungs. Mitochondrial damage increased in severity with dose-level of methylmercuric chloride.
Adult male mice of the ICR/Swiss Webster strain received a single intragastric administration of methylmercuric chloride 1,000 ppm, at dose levels of 5,10,15,20,25 and 30 mg/kg of body weight. The animals were killed six hours later. Tissue samples from the duodenum were fixed in 10% neutral buffered formalin for light microscopy. Chromosome clumping was observed in dividing cells at all dose levels, resembling a C-mitotic effect. It would lead to reduced mitotic cell formation on account of the subsequent lysis of the arrested metaphases. The cytostatic effect was brought about by the inactivation of the microtubule spindle fiber polymerization mechanism induced by methylmercuric chloride. There was a direct positive correlation between the varying dose levels of methylmercury and the proportion of cells arrested in metaphase in the crypts of the duodenum.
The chick embryo is considered a highly sensitive system for the screening of drugs for possible teratogenicity. The effects of varying concentrations of ethanol on the early development of chick embryos were studied. The mean weight of embryos exposed to ethanol was reduced compared to that of the control groups, but the difference was not significant. However, embryolethality and the incidence of abnormal embryos were significantly increased and related to the dose of ethanol.
Pregnant Sprague-Dawley rats were treated subcutaneously with PGE2 at doses of 50, 100 and 200 micrograms on gestational days 5 through 8. Control animals received physiological saline in a similar manner. On day 20 of gestation the animals were anaesthetized and fetuses were removed by hysterotomy. All fetuses recovered were alive and appeared normal. The incidence of fetal resorptions was not significantly increased. Visceral abnormalities and skeletal defects were not observed in the offspring. Also, the mean weight of treated fetuses was not significantly different from that of the corresponding controls.
The influence of both alcohol and caffeine on early embryonic development was investigated in pregnant rats. Compared to the corresponding controls, a high incidence of resorptions and abnormal embryos was induced following treatment of the animals with alcohol (0.015 ml/g body weight, 12.5% v/v, i.p.) on gestational days 6 through 12 and with caffeine (25 mg/kg body weight, i.v.) on gestational day 10. In addition, embryonic growth was severely affected. Reduction of placental blood circulation and impairment of cellular proliferation may account for the observed deleterious effects on the embryo.
Because cigarette smoking is considered to be deleterious to the fetus and caffeine is held in suspect as a potential human teratogen, the combined effects of caffeine and nicotine on early chick embryos were investigated. Treatment of the embryos at 48 h incubation with both caffeine (1 mg) and nicotine (1 mg) resulted in a high incidence of embryonic death and developmental defects. At 72 h incubation teratogenicity was potentiated following the same treatment. Embryonic growth was not affected. Embryotoxic interactions of this nature might account for congenital anomalies of doubtful etiology.
The mechanism of alcohol-induced dysmorphogenesis is not clear. Pyrazole is a potent inhibitor of alcohol dehydrogenase. Treatment of chick embryos at 96 h incubation with pyrazole (0.1 mg) and ethanol (0.1 ml, 40-60% v/v) enhanced the embryopathic response, compared with individual treatments. The results suggest that ethanol itself is embryotoxic.
The combined effects of ethanol (20 and 40%, 0.1 ml/egg) and caffeine (0.5 and 1 mg/egg) on early chick embryos were investigated. After treatment with 0.5 mg caffeine and 20% ethanol at 48 h incubation, teratogenicity was potentiated, but without affecting embryonic growth. Embryotoxic interactions of this nature might account for congenital defects of doubtful etiology.
A case of unilateral absence of the breast and nipple in a male, accompanied by partial absence of the pectoralis major muscle, is discussed.
There is increasing concern about the potential teratogenic effects of caffeine. Laboratory rodents were widely used for the teratological evaluation of caffeine. However, few studies have been carried out in non-mammalian organisms. Caffeine, dissolved in sterile water, was injected into the air sacs of fertile White Leghorn chick eggs at doses of 100, 200, 300, 400, 500, 700, 900, and 1,100 micrograms per egg. Control eggs were injected with an equivalent volume of sterile water (0.1 ml/egg). The embryos were treated at either 48, 72, or 96 hours incubation. On day 9, live embryos were recovered and examined for external malformations after staging and weighing. Treatment with 400 and 1,100 micrograms caffeine at 48 hours incubation resulted in a significantly high incidence of abnormal embryos, compared to the controls. The most common malformations included reduced body, microphthalmia, exencephaly, everted viscera and short neck. A significant number of embryos died following treatment with 1,100 micrograms caffeine at 48 hours incubation, and 400 and 700 micrograms at 72 hours incubation. Embryonic growth was not affected. Even though it is not possible to extrapolate these findings directly to humans, moderation in the consumption of caffeine-containing beverages during pregnancy is recommended.
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Mercury is a major environmental pollutant and a proven teratogen in both animals and man. Different dose levels of methylmercuric chloride (30, 25, 15 and 5 mg/kg of body weight) were administered to pregnant ICR strain mice on day 9 of pregnancy. On gestational day 18 the animals were laparotomized. A significant increase in fetal toxicity was observed at all dose levels, except following treatment with 5 mg/kg. A marked reduction in the mean weight of fetuses from treated animals (5 mg/kg) was observed compared to the controls. Higher levels of mercury were found in maternal blood and in fetal tissues of treated animals compared to the corresponding controls. Chromosome stickiness and clumping were observed in all tissues examined (e.g., bone marrow, spleen, lung, liver) from the fetuses of treated animals. The frequency of SCEs'/cell in bone marrow cells was similar to that of controls. The results demonstrate that methylmercuric chloride, the most toxic of mercuric compounds, causes chromosome stickiness and clumping leading to reduced mitotic divisions.
The teratogenic potential of alcohol in humans has now been confirmed, and a characteristic pattern of anomalies (Fetal Alcohol Syndrome) is found in infants born to mothers who are chronic alcoholics. The pathogenesis of the fetal alcohol syndrome is unclear: very little is known about the way alcohol acts during pregnancy and alters fetal growth and morphogenesis. The objective of this investigation was to determine the effects of a widely used ethanol liquid diet in the pregnant rat. The ethanol liquid test diet is based on the Lieber-De Carli formula. 20 Sprague-Dawley rats were matched closely by weights and assigned in pairs to either an alcohol treated or a pair-fed control group. Control animals received the same amount of the liquid diet with maltose-dextrins substituted isocalorically for the ethanol. Graduated tubes were used for the oral delivery of the diets. Ethanol was gradually introduced into the diet as follows: 100 Kcal/l, days 1-2; 200 Kcal/l, days 3-5; 350 Kcal/l, days 6-12. Following this initial treatment period, all animals were then given rodent pellets and tap water ad libitum. The mothers showed no overt signs of gross toxicity. The mean maternal weight gain of the ethanol treated animals did not differ significantly from the controls. The incidence of fetal resorptions was increased, intrauterine growth was not affected and the offspring at term appeared normal. The results indicate that moderate alcohol consumption during early gestation in the rat led to significant prenatal loss but proved to be non-teratogenic.
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The influence of PGF2 alpha on pregnancy and fetal outcome was investigated in the hamster. Following subcutaneous treatment with 50, 100, 200, 400, and 800 micrograms PGF2 alpha prenatal loss was significantly increased only at the highest dose level. The offspring of the treated animals were all alive and normal. Fetal weight was not affected. However, following intravenous injection of 100 and 200 micrograms PGF2 alpha there was a significant reduction in fetal weight, and at the 400 micrograms dose level an increase in fetal indicate that PGF2 alpha is not teratogenic in hamsters despite the apparent greater sensitivity of the hamster embryo to prostaglandin.
Pregnant Sprague-Dawley rats were treated subcutaneously with PGE2 at doses of 50, 100, and 200 microgram on gestational days five through eight. Control animals received the solvent in a similar manner. On gestational day 9 the animals were killed by intracardiac perfusion with Karnovsky's fixative, uteri were removed, and a transverse central slice from each implantation site was embedded in araldite. The conceptus was located and 2-3 micron sections were made of each implantation site and examined at the light microscopic level. No significant structural changes were induced in any of the conceptuses, but an unusually wide range of embryonic stages was detected in both the control and the experimental groups of animals.